Acute copper toxicity is exceedingly rare in small

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1 COPPER TOXICITY IN DOGS Robert H. Presley, DVM Resident, Small Animal Internal Medicine Douglass K. Macintire, DVM, MS, DACVIM, DACVECC Professor Department of Clinical Sciences Auburn University College of Veterinary Medicine Acute copper toxicity is exceedingly rare in small animals. In the few reported cases, copper toxicity has been associated with the ingestion of copper-containing solutions such as fungicides, algicides, and large-animal footbaths. Most coins produced in the United States contain a significant amount of copper, but toxicity from ingestion is exceedingly rare. Pennies manufactured after 1982 contain higher levels of zinc, which is the source of toxicity if ingested. Chronic copper toxicity is more common than acute toxicity in small animals and is usually the result of defective copper excretion pathways or copper accumulation secondary to chronic hepatitis. Although many breeds are suspected of having primary copper accumulation because of defective biliary excretion, only Bedlington terriers have been proven by DNA analysis to be affected by this disorder. The underlying cause of decreased copper excretion in other breeds is thought to be a secondary phenomenon related to cholestasis. Normal dogs generally have less than 400 ppm (µg copper/g per dry weight liver). However, as the copper levels increase, the binding capacity of metallothionein becomes exceeded, allowing for release of free copper into the hepatic cytosol. It is suspected that the free copper then damages the mitochondria, initiating reactive oxygen species formation and lipid peroxidation and leading to hepatocyte death. Morphologic evidence of direct hepatic injury occurs as concentrations of copper exceed 2,000 ppm, although submorphologic changes may occur at much lower levels. Concentrations greater than 2,000 ppm are most likely direct causes of hepatic injury, and levels below 1,000 ppm are most likely secondary to chronic hepatitis and cholestasis. DIAGNOSTIC CRITERIA Historical Information Gender Predisposition Female Doberman pinschers appear to be more commonly affected with chronic active hepatitis than males. No predisposition occurs in other breeds. Age Predisposition Bedlington terriers and cocker spaniels appear to be affected at very young ages (younger than 2 years of age). Other predisposed breeds typically develop clinical signs between 3 and 7 years of age. Breed Predisposition Bedlington terriers, West Highland white terriers, Doberman pinschers, cocker spaniels, Labrador retrievers, Dalmatians, Skye terriers. Owner Observations Acute toxicity: Owners may witness ingestion of copper-containing compounds or treated water. However, owners most commonly report an acute onset of gastrointestinal (GI) upset, including anorexia, vomiting, diarrhea, or corrosive oral injury. Patients typically exhibit more nonspecific signs attributable to liver failure, such as lethargy, weight loss, polyuria or polydipsia, icterus, or abdominal distention. Other Historical Considerations/Predispositions Acute toxicity is more likely to occur in areas near private ponds, golf courses, or ornamental fountains where fungicides or algicides are added to water to prevent contamination. Affected animals may have access to barns housing large animals because copper compounds are commonly used to treat hoof injury. Physical Examination Findings Acute toxicity: Dehydration, stomatitis or oral ulceration, icterus. Varies with the stage of disease; however, clinical signs may develop acutely, even in chronic disease. Lethargy. Cachexia. 5

2 O N T H E N E W S F R O N T Although many breeds are suspected of having primary copper excretion defects, it has only been proven by DNA analysis in Bedlington terriers. An autosomal recessive defect in the MURR1 gene on chromosome 10, which prevents proper excretion of copper into bile, has recently been found. Veterinary Genetic Services (VetGen.com) has developed a genetic linking test for Bedlington terriers. Using a soft cheek brush, DNA is analyzed for two alleles (1 and 2) to detect diseased animals. Allele 1 is linked with a normal gene, and allele 2 is linked with disease. If a dog is 1/1, then it is 90% likely that the animal is homozygous normal. Dogs with 2/2 alleles have a 72% chance of being affected, and 24% of them are carriers. Dogs with 1/2 alleles are also considered to be carriers. This test can easily be completed by 6 to 10 weeks of age in puppies before they are placed in homes. even with the success of this testing, liver biopsy is still the current gold standard. To determine the disease status of a Bedlington terrier, a liver biopsy should be performed at 6 months and repeated at 15 months of age. Most heterozygous animals have increased copper levels at 6 months and then return to normal by 15 months of age. Homozygous affected animals continue to have increased levels at the second biopsy and should receive preventive therapy. Icterus. Ascites. Fever. Petechiae or ecchymoses. Seizures. Laboratory Findings In most cases, abnormalities are mild and consistent with dehydration caused by GI disease. Serum chemistry profile: elevations in alanine aminotransferase (ALT), alkaline phosphatase (ALP), and aspartate aminotransferase (AST) may occur if severe toxicity is caused by hepatotoxicity. Bile acids and total bilirubin may also be increased secondary to liver dysfunction, cholestasis, and, rarely, hemolysis. $ Coagulation panel: elevations in prothrombin time (PT) and partial thromboplastin time (PTT) have been reported secondary to hepatoxicity but are rare. $ Complete blood count: Anemia secondary to acute hemolysis may occur but is also rare. $ Serum chemistry profile: $ Liver enzyme activity: ALT and AST elevations most commonly occur secondary to hepatocellular damage. These values often exceed five to 18 times normal reference ranges (ALT, U/L; AST, U/L). ALP activity may also be increased because of cholestasis, but it generally does not exceed the activity of ALT or AST as seen with steroid hepatopathies. However, in end-stage disease, these values may return to or fall below normal reference ranges. Bile acids and total bilirubin: elevations may occur secondary to liver dysfunction and cholestasis or, rarely, because of intravascular hemolysis. Hypoalbuminemia and hypocholesterolemia may be present because of hepatic insufficiency. Decreased blood urea nitrogen and hyperammonemia may be present because of decreased hepatic conversion of ammonia to urea. Hypoglycemia may be present with hepatic insufficiency or secondary sepsis. Coagulation panel: $ Prolonged PT and PTT may be noted secondary to decreased hepatic production of coagulation factors. Thrombocytopenia may occur secondary to disseminated intravascular coagulation (DIC). Complete blood count: $ Anemia: Most often the patient has mild, normocytic, normochromic nonregenerative anemia secondary to chronic disease. On rare occasions, more severe anemia may occur secondary to acute hemolysis. Leukocytosis: If present, it is generally a mild, mature neutrophilia. Thrombocytopenia: The degree of thrombocytopenia varies. Most commonly, the value is within reference range unless secondary DIC develops. Urinalysis: $ Isosthenuria often occurs secondary to polyuria and polydipsia and decreased hepatic urea production. Bilirubinuria may be present if total bilirubin exceeds renal threshold. 6 J A N U A R Y / F E B R U A R Y V O L U M e

3 Hemoglobinuria is extremely rare but is possible if intravascular hemolysis occurs. Serum copper and ceruloplasmin concentrations: Unlike with Wilson s disease (an inherited and potentially fatal copper storage disease in humans), these values are normal in dogs with chronic copper toxicity. $ Other Diagnostic Findings Abdominal radiography is often unremarkable unless microhepatia is present with chronic toxicity or primary hepatitis. Generalized loss of serosal detail may occur if ascites is present. $ Abdominal ultrasonography: With chronic disease, the liver often has generalized hyperechogenicity because of fibrotic change. Less commonly, hyperor hypoechoic nodules may be present and may represent functional islands of hepatic tissue or areas of extramedullary hematopoiesis. If fibrosis is severe, multiple acquired portosystemic shunts or ascites may be evident. $ Histopathology: $$ $$$ On routine hematoxylin and eosin stains, hepatitis is characterized by lymphocytic plasmacytic inflammation with piecemeal necrosis (necrosis of hepatocytes adjacent to the periportal tract) and occasional bridging necrosis. Variable amounts of fibrosis and cirrhosis occur depending on the stage of disease. Histochemical stains such as rhodanine and rubeanic acid can be used for semiquantitative evaluation of copper accumulation in the liver. Copper-containing lysosomes can typically be detected when values exceed 400 ppm. In animals with a primary copper excretion defect, these lysosomes tend to accumulate in a centrilobular pattern. In contrast, copper accumulation secondary to chronic hepatitis tends to have a periportal distribution consistent with cholestasis. Hepatic copper content can be definitively quantitated by atomic absorption spectroscopy. Summary of Diagnostic Criteria Acute toxicity: Diagnosis may be confirmed with owner observation of ingestion. The presence of stomatitis and oral ulceration with acute GI disease should raise suspicion of acute toxicity. Histopathology or hepatic copper quantification is the gold standard for diagnosis at this time. However, DNA analysis for specific breeds is now being developed, which may allow treatment to be initiated before development of hepatitis. RESOURCE LIST Colorado State University s diagnostic laboratory uses atomic absorption spectroscopy to definitively quantitate hepatic copper content. The service is offered for both needle and surgical biopsy samples. The laboratory can be reached by phone at Mild elevation of ALT or AST in predisposed breeds warrants a thorough diagnostic workup to minimize long-term effects. Diagnostic Differentials Zinc toxicity: With ingestion of pennies (or other coins), clinicians may often attribute clinical signs, such as acute hemolysis, to copper toxicity when zinc toxicity is the true cause. Hemolysis secondary to copper toxicity is extremely rare. Acute gastroenteritis is most commonly seen in patients with acute toxicity. Other causes of GI upset (e.g., foreign body, parvovirus infection in young animals, dietary indiscretion) should be evaluated. Vitamin K antagonism: Although rare, bleeding diathesis may occur, resulting in prolongation of clotting times (PT and PTT) with acute copper toxicity. However, if this develops, it is associated with fulminant liver failure, which should be apparent on the serum chemistry profile. Generally, liver enzyme activity remains normal with vitamin K antagonism. Chronic active hepatitis: Copper accumulation may occur in many breeds because of chronic active hepatitis. Copper quantification of liver biopsies is crucial in determining whether copper excess is the inciting cause of disease or secondary to cholestasis. Generally, copper levels above 2,000 ppm are consistent with primary disease, and levels below 1,000 ppm indicate secondary disease. Portosystemic shunt: Laboratory values and clinical signs in animals with portosystemic shunt may be similar to those seen in chronic copper toxicity. However, the patient s age and breed can be instrumental in designing a diagnostic protocol. Typically, only Bedlington terriers and possibly cocker spaniels develop laboratory or clinical abnormalities before 2 years of age. However, many patients with end-stage hepatitis may develop multiple shunts if fibrosis becomes severe. Hepatotoxins: Other hepatotoxins (e.g., sago palm, drug toxicity) may cause a similar presentation. 7

4 Often these toxins can be easily differentiated by previous exposure or administration of medications. Neoplasia: Hepatic or biliary neoplasia should be ruled out using techniques such as abdominal radiography or ultrasonography, especially in older animals with apparent liver disease. TREATMENT RECOMMENDATIONS Initial Treatment Oral administration of milk or activated charcoal should be performed to minimize epithelial damage if the animal is not vomiting. Chelating agents: $ D-penicillamine: mg/kg PO q12h on an empty stomach. Trientine: mg/kg PO q12h on an empty stomach. Dietary restriction: Most commercial diets contain copper levels that are in excess for dogs with primary copper excretion defects. Commercial diets such as royal Canin Veterinary Diet Canine Hepatic LS 14 are restricted in copper and contain many antioxidants that help control oxidative damage. Home diets may also be formulated, but ingredients such as shellfish, mushrooms, organ meats, nuts, legumes, and cereals high in copper should be avoided. Protein restriction should also be implemented if the patient has signs of hepatic encephalopathy. $ Chelating agents are most commonly used to reduce hepatic copper levels. D-penicillamine: mg/kg PO q12h on an empty stomach. $ Trientine: mg/kg PO q12h on an empty stomach. $ Zinc therapy may be used as a primary therapy but is most commonly used for maintenance therapy after primary decoppering with D-penicillamine or trientine has been performed. To prevent copper deficiency, it is recommended that zinc therapy not be combined with these drugs. Zinc decreases intestinal copper absorption by inducing synthesis of enterocyte metallothionein. Copper binds more avidly than zinc, causing increased fecal loss with normal enterocyte exfoliation. To prevent toxicity, plasma zinc levels should be measured every 2 to 3 months and maintained at 200 to 500 μg/dl. Zinc acetate: 50 mg PO q12h 30 minutes before feeding (maintenance dose). Some authors recommend 100 mg PO q12h for 3 months if other chelators are not used. $ Zinc gluconate: 1 mg/kg PO q8h 30 minutes before feeding. $ Vitamin E: IU PO q24h as an antioxidant. $ Alternative/Optional Treatments/Therapy None. S-Adenosylmethionine is a precursor of glutathione, which provides antioxidant effects in the liver. Dosage: 20 mg/kg PO q24h. $ Ursodeoxycholic acid is believed to contain some immunomodulating properties to decrease hepatic damage, most likely by displacing hydrophobic bile acids. Dosage: 15 mg/kg PO q24h. $ Prednisone may be beneficial for patients with copper toxicity secondary to chronic active hepatitis by reducing inflammation. However, if copper accumulation is primary (e.g., in Bedlington terriers and possibly other breeds), prednisone should not be used. Also, if significant fibrosis is present, prednisone may be of little to no benefit. Dosage: 2.2 mg/kg PO q24h and then tapered as liver enzyme activity improves. $ Supportive Treatment Fluid therapy should be initiated if the patient is dehydrated or in shock. Care must be taken with aggressive crystalloid therapy because many patients with liver disease have hypoalbuminemia, which may potentiate ascites or edema. Colloidal support may be beneficial in these circumstances. $ Blood products: Fresh whole blood or fresh-frozen plasma may be required for patients with coagulation perturbances. Whole blood or packed red blood cells may be beneficial in rare occurrences of hemolysis. Caution should be used in patients with clinical signs consistent with hepatic encephalopathy because stored blood products may contain high levels of ammonia. $ Antiemetics may be beneficial in animals that are vomiting. $ Gastroprotectants: H 2 blockers, proton pump blockers, or sucralfate may be beneficial in animals with acute copper toxicity; many patients with hepatic failure are predisposed to GI ulceration. $ Antibiotics are generally recommended in patients with acute toxicity because bacterial translocation may occur secondary to caustic GI ulceration. $ Patient Monitoring Most patients with acute copper toxicity only exhibit GI signs and recover with supportive ther- 8 J A N U A R Y / F E B R U A R Y V O L U M e

5 apy. However, liver enzymes and hematocrit should be monitored closely to ensure that hepatotoxicity or hemolysis does not occur. These complications are uncommon but may occur if excessive copper levels are absorbed. Liver enzyme activity should be measured at least two to four times a year in animals with chronic copper toxicity and in predisposed breeds. If zinc therapy has been instituted, plasma levels should be measured every 2 to 3 months. Home Management Owners of predisposed breeds should be educated on the severity of chronic copper toxicity, and preventive measures should be initiated early in the animal s life. Dogs should not be allowed access to ponds, lakes, or fountains treated with copper-containing fungicides or algicides. Copper chelators and zinc must be given on an empty stomach. Giving these medications with food substantially decreases their efficacy. Milestones/Recovery Time Frames Acute toxicity: Most animals with acute copper toxicity recover within 3 to 5 days as the corrosive lesions in the GI tract resolve. Chronic toxicity, whether primary or secondary to chronic hepatitis, is typically a lifelong disease. Unfortunately, most animals that are presented with clinical signs of hepatic failure may succumb to disease within days to a few months because of the severity of hepatic fibrosis. However, with early diagnosis and treatment, many of these patients survive for months to years. For example, if copper accumulation is detected at an early age, many Bedlington terriers may live a normal lifespan if treatment is initiated early. Treatment Contraindications Emesis is not recommended if clinical signs are present because of the caustic nature of copper salts. Vitamin C: Although vitamin C has antioxidant properties, it has been shown to promote further lipid peroxidation in the presence of copper. $ PROGNOSIS Favorable Criteria Acute toxicity: Clinical signs only attributable to GI ulceration. Diagnosis before liver enzyme elevation (Bedlington terriers). Decrease in liver enzyme activity with therapy. Unfavorable Criteria Acute toxicity: Liver enzyme elevation, acute hemolysis. Chronic toxicity: Severe liver fibrosis or cirrhosis, ascites, coagulation abnormalities, hepatic encephalopathy. RECOMMENDED READING Hoffmann G, van den Ingh TS, Bode P, rothuizen J: Copper-associated chronic hepatitis in Labrador retrievers. J Vet Intern Med 20: , Oswiler GD: Toxicology. Philadelphia, Lippincott Williams and Wilkins, 1996, pp Twedt DC: Copper-associated liver disease in the dog. Proc ACVIM: , Ubbink GJ, Van den Ingh TS, yuzbasiyan-gurkan V, et al: Population dynamics of inherited copper toxicosis in Dutch Bedlington terriers ( ). J Vet Intern Med 14: , Webb CB, Twedt DC, Meyer DJ: Copper-associated liver disease in Dalmations: A review of 10 dogs ( ). J Vet Intern Med 16: , Willard MD: Inflammatory canine hepatic disease, in ettinger SJ, Feldman ec (eds): Textbook of Veterinary Internal Medicine. Philadelphia, WB Saunders, 2004, pp